Do clinical outcome measures assess consumer-defined recovery?
There is an international call for mental health services to become recovery-oriented, and also to use evidence-based practices. Addressing this call requires recovery-oriented measurement of outcomes and service evaluation. Mental health consumers view recovery as leading as meaningful life, and have criticised traditional clinical measures for being too disability-oriented. This study compares three measures of consumer-defined recovery from enduring mental illness: the Recovery Assessment Scale, the Mental Health Recovery Measure and the Self-Identified Stage of Recovery, with four conventional clinical measures. Correlational analyses supported the convergent validity of the recovery measures, although certain subscales were unrelated to each other. More importantly, little relationship was found between consumer-defined recovery and the clinical measures. Analyses of variance revealed that scores on the recovery measures increased across self-identified stage of recovery, but scores on most clinical measures did not improve consistently across stage of recovery. The findings demonstrate the qualitative difference between the two types of measures, supporting the claim by consumers that clinical measures do not assess important aspects of recovery. There is a need for further research and refinement of recovery measurement, including assessment of stages of recovery, with the aim of including such measures as an adjunct in routine clinical assessment, service evaluation and research.


Two novel targets of the MAP kinase Kss1 are negative regulators of invasive growth in the yeast Saccharomyces cerevisiae.
Haploid cells of budding yeast Saccharomyces cerevisiae respond to mating pheromones by inducing genes required for conjugation, arresting cell cycle progression, and undergoing morphological changes. The same cells respond to nutrient deprivation by altering budding pattern and inducing genes required for invasive growth. Both developmental alternatives to vegetative proliferation require the MAP kinase Kss1 and the transcriptional transactivator Ste12. Using a two-hybrid screen for gene products that interact with Kss1, two homologous and previously uncharacterized loci (DIG1 and DIG2, for down-regulator of invasive growth) were identified. DIG2 is pheromone-inducible, whereas DIG1 is constitutively expressed. Dig1 colocalizes with Kssl in the nucleus, coimmunoprecipitates with Kss1 from cell extracts in a pheromone-independent manner, and is phosphorylated by Kss1 in immune complexes in a pheromone-stimulated manner. Kss1 binds specifically to a GST-Dig1 fusion in the absence of any other yeast protein. Using the two-hybrid method, both Dig1 and Dig2 also interact with the other MAP kinase of the pheromone response pathway, Fus3. However, neither dig1 or dig2 single mutants, nor a dig1 dig2 double mutant, have a discernible effect on mating. In contrast, dig1 dig2 cells constitutively invade agar medium, whereas a dig1 dig2 ste12 triple mutant does not, indicating that Dig1 and Dig2 share a role in negatively regulating the invasive growth pathway. High-level expression of Dig1 suppresses invasive growth and also causes cells to appear more resistant to pheromone-imposed cell cycle arrest. Ste12 also binds specifically to GST-Dig1 in the absence of any other yeast protein. Collectively, these findings indicate that Dig1, and most likely Dig2, are physiological substrates of Kssl and suggest that they regulate Ste12 function by direct protein-protein interaction.


Medicine use of elderly Chinese and Vietnamese immigrants and attitudes to home medicines review.
There is a paucity of research into the perceptions of elderly Australian ethnic minorities towards public health services related to quality use of medicines. Among the six fastest growing ethnic groups in Australia, the Mandarin-speaking Chinese and Vietnamese constitute the largest elderly populations with poor English skills. This paper investigates the relationships of elderly Chinese and Vietnamese migrants with medicines, general practitioners and pharmacists, and how these relationships influence their awareness and attitudes of the home medicines review (HMR) program. Two semi-structured focus groups were held with a total of 17 HMR-eligible patients who have never received a HMR, one with Chinese and one with Vietnamese respondents, each in the respective community language. Confusion about medications and an intention to have a HMR were pronounced among all participants although none of them had heard of the program before participating in the focus groups. Respondents reported difficulties locating a pharmacist who spoke their native language, which contributed to an increased unmet need for medicine information. The Chinese group additionally complained about a lack of support from their general practitioners in relation to their medicine concerns and was adamant that they would prefer to have a HMR without the involvement of their general practitioner. Our results indicate a distinct HMR need but not use among elderly Chinese and Vietnamese eligible patients with poor English skills. Home medicines review service use and perceived medication problems are likely to improve with an increasing availability of bilingual and culturally sensitive health care providers.


Ethylene-induced gene expression, enzyme activities, and water soaking in immature and ripe watermelon (Citrullus lanatus) fruit.
Watermelon fruit exhibit acute softening and placental-tissue water soaking following short exposure to exogenous ethylene. Experiments were performed to address transcript abundance and activities of cell wall and membrane hydrolases in placental tissue in response to treatment of watermelon fruit with ethylene. Watermelon fruit were harvested at immature and full-ripe stages and exposed to 50 microL L(-1) ethylene for 6 days at 20 degrees C. Ethylene affected the abundance of transcripts for PME (EC 188.8.131.52), and alpha-(EC 18.104.22.168) and beta-GAL (EC 22.214.171.124) but these effects were dependent on fruit maturity and appeared not to be associated with the water-soaking syndrome. PG (EC 18.104.22.168) and EXP mRNAs accumulated significantly in response to ethylene exposure. Additionally, the levels of mRNA and activities of LOX (EC 188.8.131.52), PLC (EC 188.8.131.52) and PLD (EC 184.108.40.206) were elevated in fruit of both maturity classes exposed to ethylene and were temporally associated with the visible symptoms of water soaking. The activity trends and transcript abundance in ethylene- compared with air-treated fruit indicate that PG, EXP, LOX, PLC and PLD levels increase with the onset and development of the water-soaking disorder and support the view that catabolic reactions targeting the membranes and cell-walls contribute to the disorder.


Ocular surface changes in the treatment of rosacea: comparison between low-dose oral isotretinoin and doxycycline.
To compare the impact of ocular changes between systemic treatment with doxycycline and low-dose oral isotretinoin in patients with moderate-to-severe papulopustular rosacea. Patients were randomized to receive either isotretinoin 0.3-0.4 mg/kg (group A) or doxycycline 100 mg/day (group B) for 16 weeks. Ocular symptoms were searched and evaluated, including best-corrected visual acuity (BCVA), Schirmer test, breakup time, rose bengal staining score, and meibomian gland dysfunction grading. The patients were retested at the end of treatment. The present study included 39 patients (30 females and 9 males). Best-corrected visual acuity was > 20/30 in >90% of patients in both groups and did not change after treatment. After treatment, improvement in ocular symptoms and meibomian gland dysfunction was more pronounced in group B (p<0.05); the other parameters did not reach statistical significance. Doxycycline improved meibomian gland dysfunction, ocular symptoms, and ocular surface in patients with rosacea. Even though some patients experienced worsening meibomian gland dysfunction and symptoms, no subject experienced any serious complications after administration of low-dose isotretinoin.


Chronic obstructive pulmonary disease prognostic score: A new index.
The evaluation of chronic obstructive pulmonary disease (COPD) has been shifting from spirometry to focus on the patients' overall health. Despite the existence of many COPD prognostic scales, there remains a large gap for improvement, in particular a scale that incorporates the current focus on overall health. We proposed a new prognostic scale (the COPD Prognostic Score) through discussion among the authors based on published studies. Validation was retrospective, using data from the National Emphysema Treatment Trial. The scores ranged from 0-16, where 16 indicated the poorest prognosis. We assigned 4 points each for forced expiratory volume in one second (%predicted), the modified Medical Research Council dyspnea scale, and age; 2 points for the hemoglobin level; and one point each for decreased activity and respiratory emergency admission in the last two years. The validation cohort included 607 patients and consisted of 388 men (73.9%) and 219 women (36.1%), mean age 67 ± 6 years and an average forced expiratory volume in one second (% predicted) of 27 ± 7%. A one-point increase in the score was associated with increased all-cause death, with a hazard ratio of 1.28 (95%CI: 1.21-1.36. P < 0.001). The areas under the receiver operating characteristic curves for two-year and five-year all-cause death for the new scale were 0.72 and 0.66, respectively. These values were higher than those given by the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index and age, dyspnea, airway obstruction (ADO) index. The preliminary validation for a new COPD prognostic scale: the COPD Prognostic Score was developed with promising results thus far. Above mentioned 16-point score accurately predicted 2-year and 5-year all-cause mortality among subjects who suffered from severe and very severe COPD.


Endometrioid carcinoma simultaneously involving the uterus and the fallopian tube: a clinicopathologic study of 13 cases.
Although the simultaneous presentation of endometrial and ovarian carcinomas of the endometrioid type is well described, little is known about a similar phenomenon involving the endometrium and fallopian tube (FT). We present the clinicopathologic features of 13 such cases seen in the Department of Pathology at The University of Texas M.D. Anderson Cancer Center over an 8 year period (1995 to 2002). FT tumors that could have represented luminal extension of the endometrial carcinoma or that represented an unequivocal metastasis to the FT were excluded. The patients' ages ranged from 34 to 77 years (median 54). The most common symptom was abnormal uterine/vaginal bleeding (11) and all of the patients were considered overweight or obese (mean body mass index was 41). The size of the endometrial carcinomas ranged from 0.3 to 8 cm. According to the FIGO grading of the endometrial endometrioid carcinomas, the cases were distributed as follows: Grade 1 (3) and Grade 2 (10). In 2 cases, there were also small areas of other histologic types, papillary serous carcinoma (1 case), and papillary endometrial carcinoma of intermediate grade (another case). The size of the fallopian tube carcinomas ranged from 0.2 to 17.5 cm. Seven of these tumors were located in the distal/fimbriated end of the FT. There was bilateral involvement in 2 cases. Three of the FT tumors were in situ. The grades of the fallopian tube carcinomas were as follows: Grade 1 (2), Grade 2 (6), and Grade 3 (2). In situ components were seen in all cases. One fallopian tube carcinoma was mixed with serous carcinoma. In 4 cases, there was also an endometrioid carcinoma involving the ovary, all of them with an intact ovarian capsule. Patients were treated as follows: total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) (4), TAH/BSO/chemotherapy (chemo) (4), TAH/BSO/radiation (3), and TAH/BSO/chemo/radiation (2). Follow-up ranging from 6 to 54 months was available in 10 patients: 1 patient died of disease (at 38 mo), 1 patient is alive with disease (at 9 mo), 7 patients have no evidence of disease (6 to 54 mo), and 1 patient died of metastatic endometrial carcinoma (at 9 mo). Simultaneous endometrioid carcinomas of the uterus and FT are unusual and occur primarily in obese perimenopausal women. The tumors are predominantly well or moderately differentiated with dissimilar endometrial and FT grades. The FT carcinoma is usually unilateral and located at the distal end of the tube.


Improved upper limits on the stochastic gravitational-wave background from 2009-2010 LIGO and Virgo data.
Gravitational waves from a variety of sources are predicted to superpose to create a stochastic background. This background is expected to contain unique information from throughout the history of the Universe that is unavailable through standard electromagnetic observations, making its study of fundamental importance to understanding the evolution of the Universe. We carry out a search for the stochastic background with the latest data from the LIGO and Virgo detectors. Consistent with predictions from most stochastic gravitational-wave background models, the data display no evidence of a stochastic gravitational-wave signal. Assuming a gravitational-wave spectrum of Ω_{GW}(f)=Ω_{α}(f/f_{ref})^{α}, we place 95% confidence level upper limits on the energy density of the background in each of four frequency bands spanning 41.5-1726 Hz. In the frequency band of 41.5-169.25 Hz for a spectral index of α=0, we constrain the energy density of the stochastic background to be Ω_{GW}(f)<5.6×10^{-6}. For the 600-1000 Hz band, Ω_{GW}(f)<0.14(f/900 Hz)^{3}, a factor of 2.5 lower than the best previously reported upper limits. We find Ω_{GW}(f)<1.8×10^{-4} using a spectral index of zero for 170-600 Hz and Ω_{GW}(f)<1.0(f/1300 Hz)^{3} for 1000-1726 Hz, bands in which no previous direct limits have been placed. The limits in these four bands are the lowest direct measurements to date on the stochastic background. We discuss the implications of these results in light of the recent claim by the BICEP2 experiment of the possible evidence for inflationary gravitational waves.


Facile microfluidic production of composite polymer core-shell microcapsules and crescent-shaped microparticles.
Core-shell microcapsules and crescent-shaped microparticles can be used as picolitre bioreactors for cell culture and microwells for cell trapping/immobilisation, respectively. Monodisperse polylactic acid (PLA) core-shell microcapsules with a diameter above 200μm, a shell thickness of 10μm, and 96% water entrapment efficiency were produced by solvent evaporation from microfluidically generated W/O/W emulsion drops with core-shell structure, and used to encapsulate Saccharomyces cerevisiae yeast cells in their aqueous cores. The morphological changes of the capsules stained with Nile red were studied over 14days under different osmotic pressure and pH gradients. The shell retained its integrity under isotonic conditions, but buckling and particle crumbling occurred in a hypertonic solution. When the capsules containing 5wt% aqueous Eudragit® S 100 solution in the core were incubated in 10-4M HCl solution, H+ diffused through the PLA film into the core causing an ionic gelation of the inner phase and its phase separation into polymer-rich and water-rich regions, due to the transition of Eudragit from a hydrophilic to hydrophobic state. Crescent-shaped composite microparticles with Eudragit cores and PLA shells were fabricated by drying core-shell microcapsules with gelled cores, due to the collapse of PLA shells encompassing water-rich crescent regions.


Life cycle assessment of greenhouse gas emissions from plug-in hybrid vehicles: implications for policy.
Plug-in hybrid electric vehicles (PHEVs), which use electricity from the grid to power a portion of travel, could play a role in reducing greenhouse gas (GHG) emissions from the transport sector. However, meaningful GHG emissions reductions with PHEVs are conditional on low-carbon electricity sources. We assess life cycle GHG emissions from PHEVs and find that they reduce GHG emissions by 32% compared to conventional vehicles, but have small reductions compared to traditional hybrids. Batteries are an important component of PHEVs, and GHGs associated with lithium-ion battery materials and production account for 2-5% of life cycle emissions from PHEVs. We consider cellulosic ethanol use and various carbon intensities of electricity. The reduced liquid fuel requirements of PHEVs could leverage limited cellulosic ethanol resources. Electricity generation infrastructure is long-lived, and technology decisions within the next decade about electricity supplies in the power sector will affectthe potential for large GHG emissions reductions with PHEVs for several decades.


Networking Our Way to Better Ecosystem Service Provision.
The ecosystem services (EcoS) concept is being used increasingly to attach values to natural systems and the multiple benefits they provide to human societies. Ecosystem processes or functions only become EcoS if they are shown to have social and/or economic value. This should assure an explicit connection between the natural and social sciences, but EcoS approaches have been criticized for retaining little natural science. Preserving the natural, ecological science context within EcoS research is challenging because the multiple disciplines involved have very different traditions and vocabularies (common-language challenge) and span many organizational levels and temporal and spatial scales (scale challenge) that define the relevant interacting entities (interaction challenge). We propose a network-based approach to transcend these discipline challenges and place the natural science context at the heart of EcoS research.


Effect of nutritional supplements on wound healing in home-nursed elderly: a randomized trial.
The objective was to determine whether provision of oral nutritional supplements, delivered by community nurses, could improve nutritional status and wound healing in home-nursed elderly. This was a double-blind, randomized trial in 50 elderly patients referred for wound management. Patients received 237 mL/d of 4 or 8 kJ/mL of an oral nutritional supplement for 4 wk. Nutritional status was measured with the Subjective Global Assessment and the Mini-Mental State Examination questionnaire to determine cognitive function and wound characteristics to assess healing. Differences between variables were examined with the Mann-Whitney or Student's t test for comparing two groups, one-way analysis of variance when there was more than two groups, and chi-square analysis for comparing two categorical variables. Associations between variables were examined with Pearson's correlation and regression analysis. At baseline, 34% subjects were moderately malnourished and 8% were severely malnourished. In both groups, there was significantly greater improvement in Mini-Mental State Examination scores at week 4 (95% confidence interval -2.0 to -0.001, P = 0.04) and a greater decrease in the wound effusion score (95% confidence interval -2.0 to 0.0, P = 0.045). Median length of stay did not differ between groups (P > 0.05). Malnutrition is common in elderly patients who are nursed at home for wound management. Provision of energy- and protein-dense oral supplements by community nurses is effective in improving some indices of wound healing and cognitive function in this group. Although further study is needed to determine the effect on length of stay, the nutritional needs of this vulnerable group should not be overlooked.


Sociodemographic disparities in survival from colorectal cancer in South Australia: a population-wide data linkage study.
Inequalities in survival from colorectal cancer (CRC) across socioeconomic groups and by area of residence have been described in various health care settings. Few population-wide datasets which include clinical and treatment information are available in Australia to investigate disparities. This study examines socio-demographic differences in survival for CRC patients in South Australia (SA), using a population-wide database derived via linkage of administrative and surveillance datasets. The study population comprised all cases of CRC diagnosed in 2003-2008 among SA residents aged 50-79 yrs in the SA Central Cancer Registry. Measures of socioeconomic status (area level), geographical remoteness, clinical characteristics, comorbid conditions, treatments and outcomes were derived through record linkage of central cancer registry, hospital-based clinical registries, hospital separations, and radiotherapy services data sources. Socio-demographic disparities in CRC survival were examined using competing risk regression analysis. Four thousand six hundred and forty one eligible cases were followed for an average of 4.7 yrs, during which time 1525 died from CRC and 416 died from other causes. Results of competing risk regression indicated higher risk of CRC death with higher grade (HR high v low =2.25, 95% CI 1.32-3.84), later stage (HR C v A = 7.74, 95% CI 5.75-10.4), severe comorbidity (HR severe v none =1.21, 95% CI 1.02-1.44) and receiving radiotherapy (HR = 1.41, 95% CI 1.18-1.68). Patients from the most socioeconomically advantaged areas had significantly better outcomes than those from the least advantaged areas (HR =0.75, 95% 0.62-0.91). Patients residing in remote locations had significantly worse outcomes than metropolitan residents, though this was only evident for stages A-C (HR = 1.35, 95 % CI 1.01-1.80). These disparities were not explained by differences in stage at diagnosis between socioeconomic groups or area of residence. Nor were they explained by differences in patient factors, other tumour characteristics, comorbidity, or treatment modalities. Socio-economic and regional disparities in survival following CRC are evident in SA, despite having a universal health care system. Of particular concern is the poorer survival for patients from remote areas with potentially curable CRC. Reasons for these disparities require further exploration to identify factors that can be addressed to improve outcomes.


Fatostatin Inhibits Cancer Cell Proliferation by Affecting Mitotic Microtubule Spindle Assembly and Cell Division.
The sterol regulatory element-binding protein (SREBP) transcription factors have become attractive targets for pharmacological inhibition in the treatment of metabolic diseases and cancer. SREBPs are critical for the production and metabolism of lipids and cholesterol, which are essential for cellular homeostasis and cell proliferation. Fatostatin was recently discovered as a specific inhibitor of SREBP cleavage-activating protein (SCAP), which is required for SREBP activation. Fatostatin possesses antitumor properties including the inhibition of cancer cell proliferation, invasion, and migration, and it arrests cancer cells in G2/M phase. Although Fatostatin has been viewed as an antitumor agent due to its inhibition of SREBP and its effect on lipid metabolism, we show that Fatostatin's anticancer properties can also be attributed to its inhibition of cell division. We analyzed the effect of SREBP activity inhibitors including Fatostatin, PF-429242, and Betulin on the cell cycle and determined that only Fatostatin possessed antimitotic properties. Fatostatin inhibited tubulin polymerization, arrested cells in mitosis, activated the spindle assembly checkpoint, and triggered mitotic catastrophe and reduced cell viability. Thus Fatostatin's ability to inhibit SREBP activity and cell division could prove beneficial in treating aggressive types of cancers such as glioblastomas that have elevated lipid metabolism and fast proliferation rates and often develop resistance to current anticancer therapies.


Cost-effectiveness and sustainability of lambdacyhalothrin-treated mosquito nets in comparison to DDT spraying for malaria control in western Thailand.
The cost-effectiveness of lambdacyhalothrin-treated nets in comparison with conventional DDT spraying for malaria control among migrant populations was evaluated in a malaria hyperendemic area along the Thai-Myanmar border. Ten hamlets of 243 houses with 948 inhabitants were given only treated nets. Twelve hamlets of 294 houses and 1,315 population were in the DDT area, and another 6 hamlets with 171 houses and 695 inhabitants were in the non-DDT-treated area. The impregnated net program was most cost-effective (US$1.54 per 1 case of prevented malaria). Spraying with DDT was more cost-effective than malaria surveillance alone ($1.87 versus $2.50 per 1 case of prevented malaria). These data suggest that personal protection measures with insecticide-impregnated mosquito net are justified in their use to control malaria in highly malaria-endemic areas in western Thailand.


Endothelial-Derived Extracellular Vesicles Induce Cerebrovascular Dysfunction in Inflammation.
Blood-brain barrier (BBB) dysfunction is a key hallmark in the pathology of many neuroinflammatory disorders. Extracellular vesicles (EVs) are lipid membrane-enclosed carriers of molecular cargo that are involved in cell-to-cell communication. Circulating endothelial EVs are increased in the plasma of patients with neurological disorders, and immune cell-derived EVs are known to modulate cerebrovascular functions. However, little is known about whether brain endothelial cell (BEC)-derived EVs themselves contribute to BBB dysfunction. Human cerebral microvascular cells (hCMEC/D3) were treated with TNFα and IFNy, and the EVs were isolated and characterised. The effect of EVs on BBB transendothelial resistance (TEER) and leukocyte adhesion in hCMEC/D3 cells was measured by electric substrate cell-substrate impedance sensing and the flow-based T-cell adhesion assay. EV-induced molecular changes in recipient hCMEC/D3 cells were analysed by RT-qPCR and Western blotting. A stimulation of naïve hCMEC/D3 cells with small EVs (sEVs) reduced the TEER and increased the shear-resistant T-cell adhesion. The levels of microRNA-155, VCAM1 and ICAM1 were increased in sEV-treated hCMEC/D3 cells. Blocking the expression of VCAM1, but not of ICAM1, prevented sEV-mediated T-cell adhesion to brain endothelia. These results suggest that sEVs derived from inflamed BECs promote cerebrovascular dysfunction. These findings may provide new insights into the mechanisms involving neuroinflammatory disorders.


No evidence that migratory geese disperse avian influenza viruses from breeding to wintering ground.
Low pathogenic avian influenza virus can mutate to a highly pathogenic strain that causes severe clinical signs in birds and humans. Migratory waterfowl, especially ducks, are considered the main hosts of low pathogenic avian influenza virus, but the role of geese in dispersing the virus over long-distances is still unclear. We collected throat and cloaca samples from three goose species, Bean goose (Anser fabalis), Barnacle goose (Branta leucopsis) and Greater white-fronted goose (Anser albifrons), from their breeding grounds, spring stopover sites, and wintering grounds. We tested if the geese were infected with low pathogenic avian influenza virus outside of their wintering grounds, and analysed the spatial and temporal patterns of infection prevalence on their wintering grounds. Our results show that geese were not infected before their arrival on wintering grounds. Barnacle geese and Greater white-fronted geese had low prevalence of infection just after their arrival on wintering grounds in the Netherlands, but the prevalence increased in successive months, and peaked after December. This suggests that migratory geese are exposed to the virus after their arrival on wintering grounds, indicating that migratory geese might not disperse low pathogenic avian influenza virus during autumn migration.


Effect of human immunodeficiency virus (HIV) infection on the course of syphilis and on the response to treatment.
To evaluate evidence that concurrent infection with human immunodeficiency virus (HIV) alters both the natural history of syphilis (by increasing the frequency of early neurosyphilis) and the response to penicillin. Review of major works on syphilis in the English language and files maintained since 1971, supplemented by a systematic search using Index Medicus and MEDLARS. The works mentioned above were critically reviewed for information on early neurosyphilis and, where relevant, HIV infection. The central nervous system is regularly involved in early syphilis. Standard recommended doses of benzathine penicillin provide cerebrospinal fluid levels that are probably at the borderline of efficacy, and cure relies on treatment and an adequate host immune response. Early neurosyphilis, appearing within 2 years of onset of infection with Treponema pallidum, was uncommon in the prepenicillin era and usually occurred after inadequate therapy. This complication was exceedingly rare in the first three decades of penicillin use. In contrast, in the past decade, 40 patients with HIV infection have been reported to have asymptomatic neurosyphilis, or syphilitic meningitis, cranial nerve abnormalities (predominantly in cranial nerves II and VIII), or cerebrovascular accidents, singly or together. In 40% of cases, HIV infection was first diagnosed when neurologic symptoms appeared. Of the 38 patients for whom information was available, 18 had the acquired immunodeficiency syndrome (AIDS), 7 had AIDS-related complex, and 13 had antibody to HIV. Sixteen had previously been treated for syphilis, of whom 5 (31%) had received benzathine penicillin within the previous 6 months. Preliminary data also suggest that skin lesions and VDRL (Venereal Disease Research Laboratory) antibody in HIV-infected patients with secondary syphilis respond more slowly to conventional penicillin therapy. Intensive therapy and follow-up observation is indicated for early syphilis in HIV-infected subjects. Novel approaches to treatment deserve systematic evaluation.


A Season of American Football Is Not Associated with Changes in Plasma Tau.
American football athletes are routinely exposed to sub-concussive impacts over the course of the season. This study sought to examine the effect of a season of American football on plasma tau, a potential marker of axonal damage. Nineteen National Collegiate Athletic Association (NCAA) football athletes underwent serial blood sampling over the course of the 2014-2015 season at those times in which the number and magnitude of head impacts likely changed. Non-contact sport controls (NCAA men's swim athletes; n = 19) provided a single plasma sample for comparison. No significant differences were observed between control swim athletes and football athletes following a period of non-contact (p = 0.569) or a period of contact (p = 0.076). Football athletes categorized as starters (n = 11) had higher tau concentrations than non-starters (n = 8) following a period of non-contact (p = 0.039) and contact (p = 0.036), but not higher than swimmers (p = 1.000 and p = 1.000, respectively). No difference was noted over the course of the season in football athletes, irrespective of starter status. Despite routine head impacts common to the sport of American football, no changes were observed over the course of the season in football athletes, irrespective of starter status. Further, no difference was observed between football athletes and non-contact control swim athletes following a period of non-contact or contact. These data suggest that plasma tau is not sensitive enough to detect damage associated with repetitive sub-concussive impacts sustained by collegiate-level football athletes.


Locally advanced breast cancer: is surgery necessary?
A retrospective analysis of the treatment of locally advanced breast cancer (LABC) was undertaken at Stanford Medical Center to assess the outcome of patients who did not undergo surgical removal of their tumors. Between 1981 and 1998, 64 patients with locally advanced breast cancer were treated with induction chemotherapy, radiation with or without breast surgery, and additional chemotherapy. Sixty-two (97%) patients received cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) induction chemotherapy. Induction chemotherapy was followed by local radiotherapy in 59 (92%) patients. Based on the clinical response to chemotherapy and patient preference, 44 (69%) patients received no local breast surgery. Radiotherapy was followed by an additional, non-doxorubicin-containing chemotherapy in all patients. The mean age of patients was 49 years. Of the 65 locally advanced breast cancers in 64 patients, 26 (41%) were stage IIIA, 35 (55%) were stage IIIB, and 4 (6%) were stage IV (supraclavicular lymph nodes only). Response to induction chemotherapy was seen in 59 patients (92%), with 29 (45%) achieving a complete clinical response and 30 (47%) a partial clinical response. With a mean follow-up of 51 months (range 7-187 months), 43 patients (67.2%) have no evidence of recurrent disease. Eight (12.5%) have recurred locally, and 21 (32.8%) have recurred with distant metastasis. Actuarial 5-year survival is 75%, disease-free survival is 58%, and local control rate is 87.5%. These data indicate that the routine inclusion of breast surgery in a combined modality treatment program for LABC does not appear necessary for the majority of patients who experience a response to induction chemotherapy.


Mono- and diglucuronide formation from chrysene and benzo(a)pyrene phenols by 3-methylcholanthrene-inducible phenol UDP-glucuronosyltransferase (UGT1A1).
Mono- and diphenols of chrysene and benzo(a)pyrene are suspected substrates of a 3-methylcholanthrene (MC)-inducible phenol UDP-glucuronosyltransferase (UGT1A1). Mono- and diglucuronide formation from these compounds was studied in two systems, (a) livers of MC-treated rats (homologous expression) and (b) a Chinese hamster lung fibroblast cell line (V79) containing rat UGT1A1 cDNA and stably expressing this isozyme (heterologous expression). In liver microsomes of MC-treated rats, glucuronidation of 6-hydroxychrysene was stimulated 11-fold by MC treatment. With 3,6-dihydroxychrysene, formation of its 3-hydroxy-6-monoglucuronide and of the diglucuronide was increased 24- and 310-fold, respectively. Induction factors obtained for monoglucuronide formation (but not for diglucuronide formation) were in line with published data on the increase of immunodetectable UGT1A1 protein and of its mRNA. It is suggested that the high induction factors for diglucuronide formation are the result of a combination of the induction of UGT1A1 and facilitated interaction of neighboring UGT1A1 molecules in endoplasmic reticulum membranes. Glucuronidation of 6-hydroxychrysene, 3-hydroxybenzo(a)pyrene, and 3,6-dihydroxybenzo(a)pyrene to their mono- and diglucuronides was clearly detectable in V79 cells expressing UGT1A1. However, conjugation of 3,6-dihydroxychrysene to its monoglucuronides was low and diglucuronide formation was not detectable, suggesting that UGT isozymes other than UGT1A1 are responsible for these reactions.


Potassium channel block by a tripartite complex of two cationophilic ligands and a potassium ion.
Voltage-gated potassium channels (Kv) are targets for drugs of large chemical diversity. Although hydrophobic cations block Kv channels with Hill coefficients of 1, uncharged electron-rich (cationophilic) molecules often display Hill coefficients of 2. The mechanism of the latter block is unknown. Using a combination of computational and experimental approaches, we mapped the receptor for the immunosuppressant PAP-1 (5-(4-phenoxybutoxy)psoralen), a high-affinity blocker of Kv1.3 channels in lymphocytes. Ligand-docking using Monte Carlo minimizations suggested a model in which two cationophilic PAP-1 molecules coordinate a K(+) ion in the pore with their coumarin moieties, whereas the hydrophobic phenoxyalkoxy side chains extend into the intrasubunit interfaces between helices S5 and S6. We tested the model by generating 58 point mutants involving residues in and around the predicted receptor and then determined their biophysical properties and sensitivity to PAP-1 by whole-cell patch-clamp. The model correctly predicted the key PAP-1-sensing residues in the outer helix, the P-loop, and the inner helix and explained the Hill coefficient of 2 by demonstrating that the Kv1.3 pore can accommodate two or even four PAP-1 molecules. The model further explained the voltage-dependence of block by PAP-1 and its thousand-fold selectivity for Kv1.3 over non-Kv1 channels. The 23- to 125-fold selectivity of PAP-1 for Kv1.3 over other Kv1 channels is probably due to its preferential affinity to the C-type inactivated state, in which cessation of K(+) flux stabilizes the tripartite PAP-1:K(+):PAP-1 complex in the pore. Our study provides a new concept for potassium channel block by cationophilic ligands.


Global intercomparison of polyurethane foam passive air samplers evaluating sources of variability in SVOC measurements.
Polyurethane foam passive air samplers (PUF-PAS) are the most common type of passive air sampler used for a range of semi-volatile organic compounds (SVOCs), including regulated persistent organic pollutants (POPs) and polycyclic aromatic hydrocarbons (PAHs), and emerging contaminants (e.g., novel flame retardants, phthalates, current-use pesticides). Data from PUF-PAS are key indicators of effectiveness of global regulatory actions on SVOCs, such as the Global Monitoring Plan of the Stockholm Convention on Persistent Organic Pollutants. While most PUF-PAS use similar double-dome metal shielding, there is no standardized dome size, shape, or deployment configuration, with many different PUF-PAS designs used in regional and global monitoring. Yet, no information is available on the comparability of data from studies using different PUF-PAS designs. We brought together 12 types of PUF-PAS used by different research groups around the world and deployed them in a multi-part intercomparison to evaluate the variability in reported concentrations introduced by different elements of PAS monitoring. PUF-PAS were deployed for 3 months in outdoor air in Kjeller, Norway in 2015-2016 in three phases to capture (1) the influence of sampler design on data comparability, (2) the influence of analytical variability when samplers are analyzed at different laboratories, and (3) the overall variability in global monitoring data introduced by differences in sampler configurations and analytical methods. Results indicate that while differences in sampler design (in particular, the spacing between the upper and lower sampler bowls) account for up to 50 % differences in masses collected by samplers, the variability introduced by analysis in different laboratories far exceeds this amount, resulting in differences spanning orders of magnitude for POPs and PAHs. The high level of variability due to analysis in different laboratories indicates that current SVOC air sampling data (i.e., not just for PUF-PAS but likely also for active air sampling) are not directly comparable between laboratories/monitoring programs. To support on-going efforts to mobilize more SVOC data to contribute to effectiveness evaluation, intercalibration exercises to account for uncertainties in air sampling, repeated at regular intervals, must be established to ensure analytical comparability and avoid biases in global-scale assessments of SVOCs in air caused by differences in laboratory performance.


Taste properties of potassium chloride alone and in mixtures with sodium chloride using a check-all-that-apply method.
As consumers try to reduce their sodium consumption for health purposes, the food industry seeks ways to reduce the sodium content in products while maintaining palatability. One potential solution for lowering sodium content is using potassium chloride (KCl) as a substitute. However, many people find KCl to have unpleasant off-tastes, which limits its effectiveness to replace sodium chloride (NaCl). This study examined the taste properties of KCl using a check-all-that-apply (CATA) ballot. The objectives were to see which terms people use to describe KCl and in what ways this changes in various combinations with NaCl. Panelists were served mixtures of varying NaCl and KCl concentrations, and evaluated them using a set of predetermined terms on a CATA ballot. Frequency counts were taken, and binomial and McNemar tests were performed to see which stimuli changed the most between samples. Results showed that adding KCl increased salt perception slightly, and salty was chosen more frequently when in combination with NaCl. Adding NaCl in a mixture with KCl decreases unpleasant side tastes associated with KCl, such as bitter, chemical, and metallic.


Parameters affecting conscious versus unconscious visual discrimination with damage to the visual cortex (V1).
When the visual (striate) cortex (V1) is damaged in human subjects, cortical blindness results in the contralateral visual half field. Nevertheless, under some experimental conditions, subjects demonstrate a capacity to make visual discriminations in the blind hemifield (blindsight), even though they have no phenomenal experience of seeing. This capacity must, therefore, be mediated by parallel projections to other brain areas. It is also the case that some subjects have conscious residual vision in response to fast moving stimuli or sudden changes in light flux level presented to the blind hemifield, characterized by a contentless kind of awareness, a feeling of something happening, albeit not normal seeing. The relationship between these two modes of discrimination has never been studied systematically. We examine, in the same experiment, both the unconscious discrimination and the conscious visual awareness of moving stimuli in a subject with unilateral damage to V1. The results demonstrate an excellent capacity to discriminate motion direction and orientation in the absence of acknowledged perceptual awareness. Discrimination of the stimulus parameters for acknowledged awareness apparently follows a different functional relationship with respect to stimulus speed, displacement, and stimulus contrast. As performance in the two modes can be quantitatively matched, the findings suggest that it should be possible to image brain activity and to identify the active areas involved in the same subject performing the same discrimination task, both with and without conscious awareness, and hence to determine whether any structures contribute uniquely to conscious perception.


Are unexplained vaginal symptoms associated with psychosocial distress? A pilot investigation.
Vaginal complaints cannot be definitively diagnosed in approximately one-third of women. We sought to determine if women without a diagnosis had higher levels of psychiatric disorders. This was an observational study in an urban family practice clinic. Prior to seeing a clinician, women with vaginal complaints completed the Patient Health Questionnaire (PHQ); symptoms were measured by the Vaginal Complaints Scale (VCS). Patients were then examined and treated by a family physician. At one and two weeks' time patients were contacted by phone regarding symptom resolution and clinical outcomes. We enrolled 47 patients; one patient was excluded. A diagnosis was made in 36. Eighteen had bacterial vaginosis, 16 had candida, three trichomonas, two HSV, one chlamydia; there were eight dual diagnoses. PHQ diagnoses were slightly less common in women without an identified cause for their symptoms. We obtained follow-up data from 45 subjects at one week and 34 subjects at two weeks' time. At two weeks' follow-up, 97% of subjects had complete resolution or improvement of their symptoms. Symptom improvement was equivalent among women with a diagnosis and those without. We estimate 180 subjects would be needed to detect a clinically meaningful difference in PHQ diagnoses. Our pilot study did not find an association between psychiatric diagnoses made by the PHQ and unexplained vaginal symptoms. Nearly all patients experienced rapid resolution of symptoms irrespective of whether a diagnosis had been made or not. These findings are limited primarily by the small sample size.


Layer-by-layer assembled thin films and microcapsules of nanocrystalline cellulose for hydrophobic drug delivery.
A layer-by-layer (LbL) approach has been employed for the fabrication of multilayer thin films and microcapsules having nanofibrous morphology using nanocrystalline cellulose (NCC) as one of the components of the assembly. The applicability of these nanoassemblies as drug delivery carriers has been explored by the loading of an anticancer drug, doxorubicin hydrochloride, and a water-insoluble drug, curcumin. Doxorubicin hydrochloride, having a good water solubility, is postloaded in the assembly. In the case of curcumin, which is very hydrophobic and has limited solubility in water, a stable dispersion is prepared via noncovalent interaction with NCC prior to incorporation in the LbL assembly. The interaction of various other lipophilic drugs with NCC was analyzed theoretically by molecular docking in consideration of NCC as a general carrier for hydrophobic drugs.


A Study on the Microbiological Status of Mineral Drinking Water.
Water-borne diseases constitute a major health burden in Bangladesh. The objective of this study was to assess the overall quality of mineral water samples that obtained from different shops of Dhaka city. To achieve the above-mentioned objective, methods of heterotrophic plate count (HPC) and total coliform count (TCC) were applied. Moreover, isolated colony from mineral water samples were characterized by using biochemical and antimicrobial susceptibility tests. Different water samples showed different HPC ranged from 1.0×10 to 8.00×102. Antimicrobial sensitivity test of some selected bacteria viz S. intermedius, S. aureus, S. felis and S. Saccharolyticus were performed. It was observed that Staphylococcus spp. isolates were susceptible to erythromycin, tetracycline, norfloxacin and ciprofloxacin. Furthermore, a few Staphylococcus spp. isolates were intermediate resistant to penicillin and oxacillin. However, most of the Staphylococcus spp. isolates were resistant to cefixime. The results indicate that mineral water serves as a reservoir of various bacteria and that people in Dhaka city, who are the consumers of these water, might get diseases. This study emphasizes the need for elaborated microbiological examinations of mineral drinking water commonly used in Dhaka city.


Activation of GLP-1 receptor enhances the chemosensitivity of pancreatic cancer cells.
This study aimed to determine whether and how the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide affects the chemoresistance and chemosensitivity of pancreatic cancer cells to gemcitabine in vitro and in vivo. The GLP-1R and protein kinase A (PKA) levels were compared between the human pancreatic cancer cell line PANC-1 and the gemcitabine-resistant cell line PANC-GR. The in vitro effects of liraglutide on the cell proliferation and apoptosis as well as the nuclear factor-kappa B NF-κB expression levels of PANC-GR cells were evaluated. In addition, a mouse xenograft model of human pancreatic cancer was established by s.c. injection of PANC-1 cells, and the effects of liraglutide on the chemosensitivity were evaluated in vitro and in vivo. In contrast to PANC-1 cells, PANC-GR cells exhibited lower expression levels of GLP-1R and PKA. Incubation with liraglutide dose dependently inhibited the growth, promoted the apoptosis, and increased the expression of GLP-1R and PKA of PANC-GR cells. Similar effects of liraglutide were observed in another human pancreatic cancer cell line MiaPaCa-2/MiaPaCa-2-GR. Either the GLP-1R antagonist Ex-9, the PKA inhibitor H89, or the NF-κB activator lipopolysaccharide (LPS) could abolish the antiproliferative and proapoptotic activities of liraglutide. Additionally, each of these agents could reverse the expression of NF-κB and ABCG2, which was decreased by liraglutide treatment. Furthermore, liraglutide treatment increased the chemosensitivity of pancreatic cancer cells to gemcitabine, as evidenced by in vitro and in vivo experiments. Thus, GLP-1R agonists are safe and beneficial for patients complicated with pancreatic cancer and diabetes, especially for gemcitabine-resistant pancreatic cancer.


The therapeutic potential of microdosing psychedelics in depression.
Microdosing psychedelics is the repeated use of small doses of, for example, lysergic acid diethylamide (LSD) and psilocybin, typically for a few weeks. Despite the popular and scientific attention in recent years, and claims by users that it has therapeutic value in affective disorders like depression, little scientific knowledge is available to back this. The purpose of this review was to investigate whether there are scientific grounds to state that this practice could be helpful in the treatment of affective disorders, and safe to use repeatedly. To that end, the literature (PubMed, MedLine) was searched, looking for (controlled) experimental studies with low doses of LSD and/or psilocybin, in healthy volunteers and patient samples. After a selection process and the addition of relevant articles, 14 experimental studies entered this review. Findings show that both LSD (10-20 mcg) and psilocybin (<1-3 mg) have subtle (positive) effects on cognitive processes (time perception, convergent and divergent thinking) and brain regions involved in affective processes. Besides the pleasant experience, increased anxiety and a cycling pattern of depressive and euphoric mood were also found. With regard to safety, it was demonstrated that low doses are well tolerated (in healthy volunteers) and have no-to-minimal effects on physiological measures. While it is yet unclear whether psychedelic microdosing is of therapeutic value for depression, the aforementioned effects on selective processes suggest that low doses of psychedelics could play a role in depression by inducing some kind of cognitive flexibility, which might lead to decreased rumination. While previous studies were conducted mostly in small samples of healthy volunteers, future placebo-controlled clinical trials in depressed patients are required to understand the therapeutic value of microdosing psychedelics, how this differs from therapy using full psychedelic doses, and whether different psychedelics have different effect patterns. The proposed research will give new insights into the potential of future alternative psychiatric treatment forms that are fiercely needed.


Three cases of androgen-dependent disease associated with myotonic dystrophy.
Three cases of androgen-dependent disease in females with myotonic dystrophy are described. Serum androgens in individuals affected by myotonic dystrophy are known to be lower on average than in normal controls. Despite this these three females developed diseases that are androgen dependent, including acne, hidradenitis suppurativa, androgenetic alopecia and keratosis pilaris. These cases support the hypothesis that the peripheral response to androgens rather than absolute circulating levels of androgens is important in androgen-dependent conditions.


Expanded use of sense codons is regulated by modified cytidines in tRNA.
Codon use among the three domains of life is not confined to the universal genetic code. With only 22 tRNA genes in mammalian mitochondria, exceptions from the universal code are necessary for proper translation. A particularly interesting deviation is the decoding of the isoleucine AUA codon as methionine by the one mitochondrial-encoded tRNA(Met). This tRNA decodes AUA and AUG in both the A- and P-sites of the metazoan mitochondrial ribosome. Enrichment of posttranscriptional modifications is a commonly appropriated mechanism for modulating decoding rules, enabling some tRNA functions while restraining others. In this case, a modification of cytidine, 5-formylcytidine (f(5)C), at the wobble position-34 of human mitochondrial tRNA(f5CAU)(Met) (hmtRNA(f5CAU)(Met)) enables expanded decoding of AUA, resulting in a deviation in the genetic code. Visualization of the codon•anticodon interaction by X-ray crystallography revealed that recognition of both A and G at the third position of the codon occurs in the canonical Watson-Crick geometry. A modification-dependent shift in the tautomeric equilibrium toward the rare imino-oxo tautomer of cytidine stabilizes the f(5)C34•A base pair geometry with two hydrogen bonds.


Australian survey of current practice and guideline use in adult cancer pain assessment and management: The community nurse perspective.
Cancer pain remains a major public health concern. Despite effective treatments being available to manage the majority of cancer pain, this debilitating symptom is frequently under treated. As cancer has becomes a chronic disease a range of health professionals, including community nurses in Australia are increasingly caring for people living with cancer related pain. Yet, little is known about community nurses capacity to assess and manage cancer pain in accordance with best available evidence. This study aimed to: identify the barriers and facilitators to adult cancer pain assessment and management as perceived by Australian health professionals; identify if cancer pain guidelines are currently used; identify barriers and facilitators to guideline use; and establish the need for Australian cancer pain guidelines. This article reports on community nurses' perceptions of managing cancer pain in the community setting. A cross-sectional survey was administered online. Invitations were circulated via peak bodies and clinical leaders seeking the views and experiences of health professionals involved in caring for people living with cancer pain. Descriptive statistics were used to summarise the quantitative data, and thematic content analysis were used to describe the qualitative data. Sixty-two community nurses responded to the survey, representing 29% of the total sample. These participants reported high levels of adherence to accepted cancer pain management practices in their workplace, with 71% nominating the Palliative Care Therapeutic Guideline V.3 as being most frequently used to manage community patients' cancer related pain. Key barriers to effective cancer pain management in the community were: difficulties accessing non-pharmacological interventions (89%), lack of coordination by multiple providers (89%), and impact of distance on ability to access pain-related services for patients (86%). A range of system, health professional and consumer barriers limit access to best available treatment in the community setting for people with cancer pain. A clinical pathway that gives step-by-step guidance on evidence-based practice along with an evaluation framework may be the best way of enabling community nurses to ensure their patients with cancer related pain have access to best available care.


Review of computer simulations of isotope effects on biochemical reactions: From the Bigeleisen equation to Feynman's path integral.
Enzymatic reactions are integral components in many biological functions and malfunctions. The iconic structure of each reaction path for elucidating the reaction mechanism in details is the molecular structure of the rate-limiting transition state (RLTS). But RLTS is very hard to get caught or to get visualized by experimentalists. In spite of the lack of explicit molecular structure of the RLTS in experiment, we still can trace out the RLTS unique "fingerprints" by measuring the isotope effects on the reaction rate. This set of "fingerprints" is considered as a most direct probe of RLTS. By contrast, for computer simulations, oftentimes molecular structures of a number of TS can be precisely visualized on computer screen, however, theoreticians are not sure which TS is the actual rate-limiting one. As a result, this is an excellent stage setting for a perfect "marriage" between experiment and theory for determining the structure of RLTS, along with the reaction mechanism, i.e., experimentalists are responsible for "fingerprinting", whereas theoreticians are responsible for providing candidates that match the "fingerprints". In this Review, the origin of isotope effects on a chemical reaction is discussed from the perspectives of classical and quantum worlds, respectively (e.g., the origins of the inverse kinetic isotope effects and all the equilibrium isotope effects are purely from quantum). The conventional Bigeleisen equation for isotope effect calculations, as well as its refined version in the framework of Feynman's path integral and Kleinert's variational perturbation (KP) theory for systematically incorporating anharmonicity and (non-parabolic) quantum tunneling, are also presented. In addition, the outstanding interplay between theory and experiment for successfully deducing the RLTS structures and the reaction mechanisms is demonstrated by applications on biochemical reactions, namely models of bacterial squalene-to-hopene polycyclization and RNA 2'-O-transphosphorylation. For all these applications, we used our recently-developed path-integral method based on the KP theory, called automated integration-free path-integral (AIF-PI) method, to perform ab initio path-integral calculations of isotope effects. As opposed to the conventional path-integral molecular dynamics (PIMD) and Monte Carlo (PIMC) simulations, values calculated from our AIF-PI path-integral method can be as precise as (not as accurate as) the numerical precision of the computing machine. Lastly, comments are made on the general challenges in theoretical modeling of candidates matching the experimental "fingerprints" of RLTS. This article is part of a Special Issue entitled: Enzyme Transition States from Theory and Experiment.


Management strategies for pancreatic pseudocysts.
Pancreatic pseudocysts are walled-off peripancreatic fluid collections. There is considerable uncertainty about how pancreatic pseudocysts should be treated. To assess the benefits and harms of different management strategies for pancreatic pseudocysts. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2015, Issue 9, and MEDLINE, EMBASE, Science Citation Index Expanded, and trials registers until September 2015. We also searched the references of included trials and contacted trial authors. We only considered randomised controlled trials (RCTs) of people with pancreatic pseudocysts, regardless of size, presence of symptoms, or aetiology. We placed no restrictions on blinding, language, or publication status of the trials. Two review authors independently identified trials and extracted data. We calculated the odds ratio (OR) and mean difference (MD) with 95% confidence intervals (CI) with RevMan 5, based on an available-case analysis for direct comparisons, using fixed-effect and random-effect models. We also conducted indirect comparisons (rather than network meta-analysis), since there were no outcomes for which direct and indirect evidence were available. We included four RCTs, with 177 participants, in this review. After one participant was excluded, 176 participants were randomised to endoscopic ultrasound (EUS)-guided drainage (88 participants), endoscopic drainage (44 participants), EUS-guided drainage with nasocystic drainage (24 participants), and open surgical drainage (20 participants). The comparisons included endoscopic drainage versus EUS-guided drainage (two trials), EUS-guided drainage with nasocystic drainage versus EUS-guided drainage alone (one trial), and open surgical drainage versus EUS-guided drainage (one trial). The participants were mostly symptomatic, with pancreatic pseudocysts resulting from acute and chronic pancreatitis of varied aetiology. The mean size of the pseudocysts ranged between 70 mm and 155 mm across studies. Although the trials appeared to include similar types of participants for all comparisons, we were unable to assess this statistically, since there were no direct and indirect results for any of the comparisons.All the trials were at unclear or high risk of bias, and the overall quality of evidence was low or very low for all outcomes. One death occurred in the endoscopic drainage group (1/44; 2.3%), due to bleeding. There were no deaths in the other groups. The differences in the serious adverse events were imprecise. Short-term health-related quality of life (HRQoL; four weeks to three months) was worse (MD -21.00; 95% CI -33.21 to -8.79; participants = 40; studies = 1; range: 0 to 100; higher score indicates better) and the costs were higher in the open surgical drainage group than the EUS-guided drainage group (MD 8040 USD; 95% CI 3020 to 13,060; participants = 40; studies = 1). There were fewer adverse events in the EUS-guided drainage with nasocystic drainage group than in the EUS-guided drainage alone (OR 0.20; 95% CI 0.06 to 0.73; participants = 47; studies = 1), or the endoscopic drainage group (indirect comparison: OR 0.08; 95% CI 0.01 to 0.61). Participants with EUS-guided drainage with nasocystic drainage also had shorter hospital stays compared to EUS-guided drainage alone (MD -8.10 days; 95% CI -9.79 to -6.41; participants = 47; studies = 1), endoscopic drainage (indirect comparison: MD -7.10 days; 95% CI -9.38 to -4.82), or open surgical drainage group (indirect comparison: MD -12.30 days; 95% CI -14.48 to -10.12). The open surgical drainage group had longer hospital stays than the EUS-guided drainage group (MD 4.20 days; 95% CI 2.82 to 5.58; participants = 40; studies = 1); the endoscopic drainage group had longer hospital stays than the open drainage group (indirect comparison: -5.20 days; 95% CI -7.26 to -3.14). The need for additional invasive interventions was higher for the endoscopic drainage group than the EUS-guided drainage group (OR 11.13; 95% CI 2.85 to 43.44; participants = 89; studies = 2), and the open drainage group (indirect comparison: OR 23.69; 95% CI 1.40 to 400.71). The differences between groups were imprecise for the other comparisons that could be performed. None of the trials reported long-term mortality, medium-term HRQoL (three months to one year), long-term HRQoL (longer than one year), time-to-return to normal activities, or time-to-return to work. Very low-quality evidence suggested that the differences in mortality and serious adverse events between treatments were imprecise. Low-quality evidence suggested that short-term HRQoL (four weeks to three months) was worse, and the costs were higher in the open surgical drainage group than in the EUS-guided drainage group. Low-quality or very low-quality evidence suggested that EUS-guided drainage with nasocystic drainage led to fewer adverse events than EUS-guided or endoscopic drainage, and shorter hospital stays when compared to EUS-guided drainage, endoscopic drainage, or open surgical drainage, while EUS-guided drainage led to shorter hospital stays than open surgical drainage. Low-quality evidence suggested that there was a higher need for additional invasive procedures with endoscopic drainage than EUS-guided drainage, while it was lower in the open surgical drainage than in the endoscopic drainage group.Further RCTs are needed to compare EUS-guided drainage, with or without nasocystic drainage, in symptomatic patients with pancreatic pseudocysts that require treatment. Future trials should include patient-oriented outcomes such as mortality, serious adverse events, HRQoL, hospital stay, return-to-normal activity, number of work days lost, and the need for additional procedures, for a minimum follow-up period of two to three years.


Increased expression of gelatinase (MMP-2 and MMP-9) in pterygia and pterygium fibroblasts with disease progression and activation of protein kinase C.
To study the expression of matrix metalloprotease (MMP)-2 and MMP-9 mRNA and activities in various stages of surgically excised pterygium specimens and cultured pterygium fibroblasts and to study the effects of activation of protein kinase C (PKC) on the expression of these MMPs in pterygium fibroblasts. MMP-2 and MMP-9 mRNA expression and activities in 15 pterygium tissues and cultured pterygium fibroblasts were measured by RT-PCR and zymography. Five normal conjunctiva specimens and fibroblasts were tested as the controls. Changes of expression of MMP-2 and MMP-9 of fibroblasts after the simulation of a standard PKC activator, 2-O-tetradecanoyl-phorbol-13-acetate (TPA), were studied. MMP-2 and MMP-9 expression in pterygium tissues and fibroblasts was greater than those of normal tissues and fibroblasts and was closely relevant to the progression of pterygium. In early-stage pterygium tissues and cultured fibroblasts, MMP-9 was not expressed, activated MMP-2 could not be detected, and only a small amount of latent MMP-2 was present. In advanced-stage pterygium (pterygium head passed the papillary region), MMP-9 was expressed; activated MMP-2 and a large amount of latent MMP-2 could be detected in pterygium tissues and fibroblasts. TPA stimulated the expression of MMP-2 and MMP-9 by pterygium fibroblasts isolated from early-stage specimens in a dose-dependent manner. MMP-2 and MMP-9 expression by pterygium fibroblasts is significantly increased after the progression of pterygium. Activation of the PKC signaling pathway, aside from other previously reported signaling pathways, may play a role in the development and progression of pterygium.


Management of Malnutrition in Older Patients-Current Approaches, Evidence and Open Questions.
Malnutrition is widespread in older people and represents a major geriatric syndrome with multifactorial etiology and severe consequences for health outcomes and quality of life. The aim of the present paper is to describe current approaches and evidence regarding malnutrition treatment and to highlight relevant knowledge gaps that need to be addressed. Recently published guidelines of the European Society for Clinical Nutrition and Metabolism (ESPEN) provide a summary of the available evidence and highlight the wide range of different measures that can be taken-from the identification and elimination of potential causes to enteral and parenteral nutrition-depending on the patient's abilities and needs. However, more than half of the recommendations therein are based on expert consensus because of a lack of evidence, and only three are concern patient-centred outcomes. Future research should further clarify the etiology of malnutrition and identify the most relevant causes in order to prevent malnutrition. Based on limited and partly conflicting evidence and the limitations of existing studies, it remains unclear which interventions are most effective in which patient groups, and if specific situations, diseases or etiologies of malnutrition require specific approaches. Patient-relevant outcomes such as functionality and quality of life need more attention, and research methodology should be harmonised to allow for the comparability of studies.


Evaluation of quality of life in Turkish patients with head and neck cancer.
In this study, our aim was to investigate the effect of factors, such as radiotherapy, the dose of radiotherapy, the region of radiotherapy, the age of the patient, performance, co-morbidity, the stage of the disease and the therapy modalities on the quality of life of patients with head and neck cancer. Eighty-two patients who were treated by either chemoradiotherapy or radiotherapy, at the Cumhuriyet University Faculty of Medicine, Department of Radiation Oncology, between February 2007 and September 2010, for head and neck cancer were included. The quality of life European Organisation for Research and Treatment of Cancer, Questionnaire module to be used in Quality of Life assessments in Head and Neck Cancer (EORTC QLQ-HandN35) questionnaire was conducted in all patients before starting the radiotherapy, in the middle, at the end, at 1 month and at 6 months after the treatment. According to the questionnaires at the end and at the 6th month after the radiotherapy, it was found that the age of the patient, co-morbidity, ECOG performance state, localization, type of treatment, the stage of the disease, the dose and the region of radiotherapy affect some of the symptom scales for quality of life. Quality of life was affected negatively during and after the radiotherapy. However, in the 6th month after the therapy, a significant improvement was observed in most symptoms.


Evaluation of Post-operative Meningitis: Comparison of Meningitis Caused by Acinetobacter spp. and Other Possible Causes.
To analyse postoperative meningitis (POM) after craniotomy, and to compare the clinical characteristics, treatment outcomes and mortality rates of POM that were caused by Acinetobacter spp. or other possible causes. In this study, POM cases in our hospital between 2008 and 2016 were retrospectively reviewed. Cases were divided into three groups; Acinetobacter spp. meningitis (case group), non-Acinetobacter bacterial meningitis (control group 1) and culture negative meningitis (control group 2). Demographic, clinical, laboratory features, treatment modalities and mortality rates were compared between case and control groups. A total of 112 patients with POM were included in the study. Cerebrospinal fluid (CSF) culture results were negative in 50 (44.6%) patients; bacteria were isolated from CSF of 62 (55.3%) patients. Acinetobacter spp. was isolated from 28 (45%) patients, while bacteria other than Acinetobacter spp. were detected in 34 (55%) patients. No significant differences were observed between case and control groups in terms of age, gender, comorbidity and operation type. For the case group, change of treatment according to culture result was significantly different from control groups (p < 0.001). Mortality was 55.6% in the case group, 24.2% in control group 1 (p=0.013), and 24% in control group 2 (p=0.006). In multivariate analysis, isolation of Acinetobacter spp. from CSF culture [OR < sub > adj < /sub > 5.2, 95% confidence interval (CI):1.2-22.0, p=0.026] and inappropriate treatment (OR < sub > adj < /sub > 15.7, 95%CI:3.6-68.9, p < 0.001) were determined to be independent risk factors for mortality. Postoperative meningitis, especially caused by Acinetobacter spp., and its inappropriate empirical treatment are associated with high mortality.


Protein Phosphatase 2B Dual Function Facilitates Synaptic Integrity and Motor Learning.
Protein phosphatase 2B (PP2B) is critical for synaptic plasticity and learning, but the molecular mechanisms involved remain unclear. Here we identified different types of proteins that interact with PP2B, including various structural proteins of the postsynaptic densities (PSDs) of Purkinje cells (PCs) in mice. Deleting PP2B reduced expression of PSD proteins and the relative thickness of PSD at the parallel fiber to PC synapses, whereas reexpression of inactive PP2B partly restored the impaired distribution of nanoclusters of PSD proteins, together indicating a structural role of PP2B. In contrast, lateral mobility of surface glutamate receptors solely depended on PP2B phosphatase activity. Finally, the level of motor learning covaried with both the enzymatic and nonenzymatic functions of PP2B. Thus, PP2B controls synaptic function and learning both through its action as a phosphatase and as a structural protein that facilitates synapse integrity.SIGNIFICANCE STATEMENT Phosphatases are generally considered to serve their critical role in learning and memory through their enzymatic operations. Here, we show that protein phosphatase 2B (PP2B) interacts with structural proteins at the synapses of cerebellar Purkinje cells. Differentially manipulating the enzymatic and structural domains of PP2B leads to different phenotypes in cerebellar learning. We propose that PP2B is crucial for cerebellar learning via two complementary actions, an enzymatic and a structural operation.


Hesperidin suppresses the migration and invasion of non-small cell lung cancer cells by inhibiting the SDF-1/CXCR-4 pathway.
The present study aimed to investigate the ability of hesperidin to suppress the migration and invasion of A549 cells, and to investigate the role of the SDF-1/CXCR-4 cascade in this suppression. We performed a Transwell migration assay to measure the migratory capability of A549 cells treated with 0.5% DMSO, SDF-1α, AMD3100 or hesperidin. The SDF-1 level in the culture medium was determined by an enzyme-linked immunosorbent assay (ELISA) to detect whether different concentrations of hesperidin affected SDF-1 secretion. A wound-healing assay was performed to determine the effects of different concentrations of hesperidin on the migration inhibition of A549, H460 and H1975 cells. Additionally, the effect of various hesperidin concentrations on the rate of A549 cell invasion and migration was examined with and without Matrigel in Transwell assays, respectively. Western blot analysis was used to evaluate the protein levels of CXCR-4, MMP-9, CK-19, Vimentin, p65, p-p65, p-IκB, IκB, p-Akt and Akt. RT-qPCR was used to detect the mRNA levels of CXCR-4, MMP-9, CK-19, Vimentin, p65, IκB, SDF-1 and Akt. The Transwell migration assay indicated that SDF-1α promoted A549 cell migration, while AMD3100 and hesperidin significantly inhibited the migratory capability. The wound-healing assay demonstrated that hesperidin treatment significantly reduced the rate of wound closure compared with the control group in a dose-dependent manner. Similarly, the migration and invasive abilities of A549 cells, H460 and H1975 cells treated with hesperidin were significantly decreased compared with the control group. The ELISA data suggested that hesperidin attenuated the secretion of SDF-1 from A549 cells in a dose-dependent manner. Furthermore, western blot analysis indicated that SDF-1α treatment significantly increased the levels of CXCR-4, p-p65, p-IκB and p-Akt in A549 cells. In contrast, AMD3100 or hesperidin reversed the effect induced by SDF-1α through decreasing the expression of CXCR-4. Subsequent RT-qPCR and western blot analyses also confirmed that hesperidin had a significant effect on the expression of EMT-related proteins, including MMP-9, CK-19 and Vimentin, in A549 cells. In summary, we demonstrated that hesperidin inhibited the migratory and invasive capabilities of A549 human non-small cell lung cancer cells by the mediation of the SDF-1/CXCR-4 signaling cascade, thus providing the foundation for the development of hesperidin as a safer and more effective anticancer drug for non-small cell lung cancer.


Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs.
Phytochemicals play an important role in cancer therapy. Hispolon and 26 of its analogs (9 known and 17 new) were synthesized and evaluated for their antiproliferative activities in a panel of six independent human cancer cell lines using the in vitro cell-based MTT assay. Among the hispolon analogs tested, compound VA-2, the most potent overall, produced its most significant effect in the colon cancer cell lines HCT-116 (IC₅₀ 1.4 ± 1.3 μM) and S1 (IC₅₀ 1.8 ± 0.9 μM) compared to its activity in the normal HEK293/pcDNA3.1 cell line (IC₅₀ 15.8±3.7 μM; p<0.01 for each comparison). Based on our results, VA-2 was about 9- to 11-times more potent in colon cancer cells and 2- to 3-times more potent in prostate cancer cells compared to HEK293/pcDNA3.1 cells. Morphological analysis of VA-2 showed significant reduction of cell number, while the cells' sizes were also markedly increased and were obvious at 68 h of treatment with 1 μM in HCT-116 (colon) and PC-3 (prostate) cancer cells. A known analog, compound VA-4, prepared by simple modifications on the aromatic functional groups of hispolon, inhibited prostate and colon cancer cell lines with IC₅₀ values <10 μM. In addition, hispolon isoxazole and pyrazole analogs, VA-7 and VA-15 (known), respectively, have shown significant activity with the mean ICv values in the range 3.3-10.7 μM in all the cancer cell lines tested. Activity varied among the analogs in which aromatic functional groups and β-diketone functional groups are modified. But the activity of analogs VA-16 to VA-27 was completely lost when the side chain double-bond was hydrogenated indicating the crucial role of this functionality for anticancer activity. Furthermore, many of the compounds synthesized were not substrates for the ABCB1-transporter, the most common cause of multidrug resistance in anti-cancer drugs, suggesting they may be more effective anticancer agents.


Single Voxel Proton Spectroscopy for Neurofeedback at 7 Tesla.
Echo-planar imaging (EPI) in fMRI is regularly used to reveal BOLD activation in presubscribed regions of interest (ROI). The response is mediated by relative changes in T2* which appear as changes in the image pixel intensities. We have proposed an application of functional single-voxel proton spectroscopy (fSVPS) for real-time studies at ultra-high MR field which can be comparable to the EPI BOLD fMRI technique. A spin-echo SVPS protocol without water suppression was acquired with 310 repetitions on a 7T Siemens MR scanner (TE/TR = 20/1000 ms, flip angle α = 90°, voxel size 10 × 10 × 10 mm3). Transmitter reference voltage was optimized for the voxel location. Spectral processing of the water signal free induction decay (FID) using log-linear regression was used to estimate the T2* change between rest and activation of a functional task. The FID spectrum was filtered with a Gaussian window around the water peak, and log-linear regression was optimized for the particular ROI by adoption of the linearization length. The spectroscopic voxel was positioned on an ROI defined from a real-time fMRI EPI BOLD localizer. Additional online signal processing algorithms performed signal drift removal (exponential moving average), despiking and low-pass filtering (modified Kalman filter) and, finally, the dynamic feedback signal normalization. Two functional tasks were used to estimate the sensitivity of the SVPS method compared to BOLD signal changes, namely the primary motor cortex (PMC, left hand finger tapping) and visual cortex (VC, blinking checkerboard). Four healthy volunteers performed these tasks and an additional session using real-time signal feedback modulating their activation level of the PMC. Results show that single voxel spectroscopy is able to provide a good and reliable estimation of the BOLD signal changes. Small data size and FID signal processing instead of processing entire brain volumes as well as more information revealed from the acquired total water spectrum, i.e., direct estimation of the T2* values and B0 changes, make SVPS proton spectroscopy suitable and advantageous for real-time neurofeedback studies. Particular challenges of ultra-high field spectroscopy due to the non-linearity in the spectral information, e.g., poor main magnetic field homogeneity and the absence of motion correction for the SVPS sequence may lead to the special artifacts in the control signal which still need to be addressed. The contrast to noise ratio (CNR), experimental statistic (t-values) and percent signal change were used as quality parameters to estimate the method performance. The potential and challenges of the spectroscopic approach for fMRI studies needs to be further investigated.


Consequences of a short time exposure to a sublethal dose of Flupyradifurone (Sivanto) pesticide early in life on survival and immunity in the honeybee (Apis mellifera).
Dramatic losses of pollinating insects have become of global concern, as they threaten not only key ecosystem services but also human food production. Recent research provided evidence that interactions between ecological stressors are drivers of declining pollinator health and responsible for observed population collapses. We used the honeybee Apis mellifera and conducted a series of experiments to test for long-term effects of a single short exposure to the agricultural pesticide flupyradifurone to a second environmental stressor later in life. To do this, we exposed individuals during their larval development or early adulthood to sublethal dosages of flupyradifurone (0.025 μg for larvae and 0.645 μg for imagos), either pure or as part of an agricultural formulation (Sivanto). We afterwards exposed bees to a second ecological stressor infecting individuals with 10,000 spores of the fungal gut parasite Nosema ceranae. We found that pesticide exposures significantly reduced survival of bees and altered the expression of several immune and detoxification genes. The ability of bees to respond to these latter effects differed significantly between colonies, offering opportunities to breed bees with elevated levels of pesticide tolerance in the future. We conclude that short episodes of sublethal pesticide exposures during development are sufficient to trigger effects later in life and could therefore contribute to the widespread declines in bee health.


Molecular and structural characterization of the SH3 domain of AHI-1 in regulation of cellular resistance of BCR-ABL(+) chronic myeloid leukemia cells to tyrosine kinase inhibitors.
ABL tyrosine kinase inhibitor (TKI) therapy induces clinical remission in chronic myeloid leukemia (CML) patients but early relapses and later emergence of TKI-resistant disease remain problematic. We recently demonstrated that the AHI-1 oncogene physically interacts with BCR-ABL and JAK2 and mediates cellular resistance to TKI in CML stem/progenitor cells. We now show that deletion of the SH3 domain of AHI-1 significantly enhances apoptotic response of BCR-ABL(+) cells to TKIs compared to cells expressing full-length AHI-1. We have also discovered a novel interaction between AHI-1 and Dynamin-2, a GTPase, through the AHI-1 SH3 domain. The crystal structure of the AHI-1 SH3 domain at 1.53-Å resolution reveals that it adopts canonical SH3 folding, with the exception of an unusual C-terminal α helix. PD1R peptide, known to interact with the PI3K SH3 domain, was used to model the binding pattern between the AHI-1 SH3 domain and its ligands. These studies showed that an "Arg-Arg-Trp" stack may form within the binding interface, providing a potential target site for designing specific drugs. The crystal structure of the AHI-1 SH3 domain thus provides a valuable tool for identification of key interaction sites in regulation of drug resistance and for the development of small molecule inhibitors for CML.


Toll-like receptor 3 (TLR3) plays a major role in the formation of rabies virus Negri Bodies.
Human neurons express the innate immune response receptor, Toll-like receptor 3 (TLR3). TLR3 levels are increased in pathological conditions such as brain virus infection. Here, we further investigated the production, cellular localisation, and function of neuronal TLR3 during neuronotropic rabies virus (RABV) infection in human neuronal cells. Following RABV infection, TLR3 is not only present in endosomes, as observed in the absence of infection, but also in detergent-resistant perinuclear inclusion bodies. As well as TLR3, these inclusion bodies contain the viral genome and viral proteins (N and P, but not G). The size and composition of inclusion bodies and the absence of a surrounding membrane, as shown by electron microscopy, suggest they correspond to the previously described Negri Bodies (NBs). NBs are not formed in the absence of TLR3, and TLR3(-/-) mice -- in which brain tissue was less severely infected -- had a better survival rate than WT mice. These observations demonstrate that TLR3 is a major molecule involved in the spatial arrangement of RABV-induced NBs and viral replication. This study shows how viruses can exploit cellular proteins and compartmentalisation for their own benefit.


Impact of operative time on early joint infection and deep vein thrombosis in primary total hip arthroplasty.
Infections and deep vein thrombosis (DVT) after total hip arthroplasty (THA) are challenging problems for both the patient and surgeon. Previous studies have identified numerous risk factors for infections and DVT after THA but have often been limited by sample size. We aimed to evaluate the effect of operative time on early postoperative infection as well as DVT rates following THA. We hypothesized that an increase in operative time would result in increased odds of acquiring an infection as well as a DVT. We conducted a retrospective analysis of prospectively collected data using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database from 2006 to 2015 for all patients undergoing primary THA. Associations between operative time and infection or DVT were evaluated with multivariable logistic regressions controlling for demographics and several known risks factors for infection. Three different types of infections were evaluated: (1) superficial surgical site infection (SSI), an infection involving the skin or subcutaneous tissue, (2) deep SSI, an infection involving the muscle or fascial layers beneath the subcutaneous tissue, and (3) organ/space infection, an infection involving any part of the anatomy manipulated during surgery other than the incisional components. In total, 103,044 patients who underwent THA were included in our study. Our results suggested a significant association between superficial SSIs and operative time. Specifically, the adjusted odds of suffering a superficial SSI increased by 6% (CI=1.04-1.08, p<0.0001) for every 10-minute increase of operative time. When using dichotomized operative time (<90minutes or >90minutes), the adjusted odds of suffering a superficial SSI was 56% higher for patients with prolonged operative time (CI=1.05-2.32, p=0.0277). The adjusted odds of suffering a deep SSI increased by 7% for every 10-minute increase in operative time (CI=1.01-1.14, p=0.0335). No significant associations were detected between organ/space infection, wound dehiscence, or DVT and operative time either as continuous or as dichotomized. Prolonged operative times (>90min) are associated with increased rates of superficial SSIs, but not deep SSIs, organ/space infections, wound dehiscence, or DVT. III.


The practitioners' perspective on the upside and downside of applying social capital concept in therapeutic settings.
Social capital, and more particularly the social networks that define its existence, is said to benefit health and well-being. In individuals recovering from alcohol and drug addiction, social capital accruing from social networks support treatment, recovery and maintenance. Therefore, the concept of social capital is important for public health practitioners working in recovery interventions. This qualitative study seeks to explore what practitioners perceive as the importance of social capital and how they apply the concept in interventions to support individuals recovering from drug and alcohol addiction. Eight public health practitioners involved in drug and substance abuse interventions in West Yorkshire, England, were interviewed. The results of the interview were then deductively coded using two priori themes of perceived impact of social capital on health outcomes and application of social capital theory in recovery interventions. The findings reveal that practitioners understand the impact of social capital as the effects of social networks on recovery and apply the concept in their interventions. However, the nature of interventions created based on similarities in condition (alcohol and substance addiction) and intended outcome (recovery) create bonding social capital with mixed outcomes. This paper argues that the wider benefits to service users are unintentionally inhibited by the overwhelming downsides of bonding social capital. For instance, closed support groups comprised of individuals with high similarities further exclude the already socioeconomically deprived service users from integrating and accessing resources outside their groups.


Van der Waals interactions and the limits of isolated atom models at interfaces.
Van der Waals forces are among the weakest, yet most decisive interactions governing condensation and aggregation processes and the phase behaviour of atomic and molecular matter. Understanding the resulting structural motifs and patterns has become increasingly important in studies of the nanoscale regime. Here we measure the paradigmatic van der Waals interactions represented by the noble gas atom pairs Ar-Xe, Kr-Xe and Xe-Xe with a Xe-functionalized tip of an atomic force microscope at low temperature. Individual rare gas atoms were fixed at node sites of a surface-confined two-dimensional metal-organic framework. We found that the magnitude of the measured force increased with the atomic radius, yet detailed simulation by density functional theory revealed that the adsorption induced charge redistribution strengthened the van der Waals forces by a factor of up to two, thus demonstrating the limits of a purely atomic description of the interaction in these representative systems.


Genome-wide structural and evolutionary analysis of the P450 monooxygenase genes (P450ome) in the white rot fungus Phanerochaete chrysosporium: evidence for gene duplications and extensive gene clustering.
Phanerochaete chrysosporium, the model white rot basidiomycetous fungus, has the extraordinary ability to mineralize (to CO2) lignin and detoxify a variety of chemical pollutants. Its cytochrome P450 monooxygenases have recently been implied in several of these biotransformations. Our initial P450 cloning efforts in P. chrysosporium and its subsequent whole genome sequencing have revealed an extraordinary P450 repertoire ("P450ome") containing at least 150 P450 genes with yet unknown function. In order to understand the functional diversity and the evolutionary mechanisms and significance of these hemeproteins, here we report a genome-wide structural and evolutionary analysis of the P450ome of this fungus. Our analysis showed that P. chrysosporium P450ome could be classified into 12 families and 23 sub-families and is characterized by the presence of multigene families. A genome-level structural analysis revealed 16 organizationally homogeneous and heterogeneous clusters of tandem P450 genes. Analysis of our cloned cDNAs revealed structurally conserved characteristics (intron numbers and locations, and functional domains) among members of the two representative multigene P450 families CYP63 and CYP505 (P450foxy). Considering the unusually complex structural features of the P450 genes in this genome, including microexons (2-10 aa) and frequent small introns (45-55 bp), alternative splicing, as experimentally observed for CYP63, may be a more widespread event in the P450ome of this fungus. Clan-level phylogenetic comparison revealed that P. chrysosporium P450 families fall under 11 fungal clans and the majority of these multigene families appear to have evolved locally in this genome from their respective progenitor genes, as a result of extensive gene duplications and rearrangements. P. chrysosporium P450ome, the largest known to date among fungi, is characterized by tandem gene clusters and multigene families. This enormous P450 gene diversity has evolved by extensive gene duplications and intragenomic recombinations of the progenitor genes presumably to meet the exceptionally high metabolic demand of this biodegradative group of basidiomycetous fungi in ecological niches. In this context, alternative splicing appears to further contribute to the evolution of functional diversity of the P450ome in this fungus. The evolved P450 diversity is consistent with the known vast biotransformation potential of P. chrysosporium. The presented analysis will help design future P450 functional studies to understand the underlying mechanisms of secondary metabolism and oxidative biotransformation pathways in this model white rot fungus.


Two dimensional array of piezoresistive nanomechanical Membrane-type Surface Stress Sensor (MSS) with improved sensitivity.
We present a new generation of piezoresistive nanomechanical Membrane-type Surface stress Sensor (MSS) chips, which consist of a two dimensional array of MSS on a single chip. The implementation of several optimization techniques in the design and microfabrication improved the piezoresistive sensitivity by 3~4 times compared to the first generation MSS chip, resulting in a sensitivity about ~100 times better than a standard cantilever-type sensor and a few times better than optical read-out methods in terms of experimental signal-to-noise ratio. Since the integrated piezoresistive read-out of the MSS can meet practical requirements, such as compactness and not requiring bulky and expensive peripheral devices, the MSS is a promising transducer for nanomechanical sensing in the rapidly growing application fields in medicine, biology, security, and the environment. Specifically, its system compactness due to the integrated piezoresistive sensing makes the MSS concept attractive for the instruments used in mobile applications. In addition, the MSS can operate in opaque liquids, such as blood, where optical read-out techniques cannot be applied.


[Endodontics in motion: new concepts, materials and techniques 4. Root canal disinfection in 2015].
Apical periodontitis is an inflammatory response around the root tip of a tooth to microbial infection of the root canal system. Therefore, disinfection of the root canal system is the most important aim of root canal treatment. There are various mechanical and chemical ways to clean and disinfect. Most methods, however, cannot be relied upon to fully decontaminate in all cases. There are problems, for example, with the proper concentrations of disinfectant agents, like sodium hypochlorite. But the more recent agents, like ethylenediaminetetraacetic acid, calcium hydroxide or antibiotic pastes also have disadvantages, which are mostly a result of poor access of the irrigant to the biofilm bacteria in the affected root canals. Currently, a new strategy with a modified salt solution is under investigation that offers the prospect of being used as a root canal irrigant. At this moment the preferred treatment still seems to be to remove infected tissue as much as possible and to create access for irrigation procedures. The best results are achieved with 1-2% sodium hypochlorite as a disinfectant, possibly alternating with ethylenediaminetetraacetic acid as a cleansing agent. There is no scientific evidence for the successful use of calcium hydroxide.


Comparing the Effects of Stroke-Appearing and Stroke-Disappearing on Learning the Order of Strokes in Chinese Characters.
Different approaches to stimulating perceptions in learning can be easily designed with technology-enhanced learning systems. This study aimed to explore how different approaches can influence learners' perceptions that may negatively or positively affect their learning performance of writing Chinese characters using the correct Chinese order of strokes (COS). We therefore designed an e-learning system which was subdivided into two modes: stroke-appearing (i.e., using red to mark incorrect strokes) and stroke-disappearing (i.e., using blanks to mark incorrect strokes) to indicate strokes written in the incorrect order. We then investigated the modes that would facilitate a higher level of attention and better learning outcomes. A total of 10 third-grade elementary school students participated in the experiment, divided into two test groups. Their EEG data were collected, and time series analysis and t-tests were utilized to analyze the differences. The results indicated that: (1) there was a significant difference in the attention levels of the students practicing with the stroke-appearing and stroke-disappearing modes when learning COS, and (2) there was a significant difference in the learning outcomes of the students practicing with the stroke-appearing and stroke-disappearing modes when learning COS. These findings support the specific role of stroke order knowledge in learning Chinese characters and the need for the design of an effective method for teaching children to learn Chinese characters.


Physiological condition differentially affects the behavior and survival of two populations of sockeye salmon during their freshwater spawning migration.
Recently, a segment of the Adams-Shuswap sockeye salmon (Oncorhynchus nerka) population initiated freshwater migration several weeks earlier than historically recorded, resulting in high mortality rates. The comigrating Chilko population maintained their historic river entry timing and did not experience elevated mortality. To test the hypothesis that population-specific differences in physiological condition would differentially influence behavior and survival when exposed to fisheries capture stress, we physiologically sampled individuals from both populations at the onset of the freshwater phase of their reproductive migration and tracked the remainder of their migrations using radio telemetry. Adams-Shuswap individuals had slower migration rates and were less likely to reach natal subwatersheds relative to Chilko individuals. Metabolic and osmoregulatory impairment was related to mortality for Adams-Shuswap individuals but not for Chilko individuals. Similarly, physiological condition correlated with migration rate for Adams-Shuswap but not Chilko fish. Survival to natal subwatersheds was 1.9 times higher for Chilko relative to Adams-Shuswap, a result that did not emerge until individuals approached natal subwatersheds several days after the stressor was applied. We conclude that physiological condition differentially affects the behavior and survival of these two populations, which may be a consequence of the early-entry phenomenon by a segment of the Adams-Shuswap population.